21-36964534-A-G

Variant names:

• chr21-36964534-A-G
• rs1571700
• NM_001352514.2:c.195+1910T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001352514.2(HLCS):​c.195+1910T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.61 in 152,056 control chromosomes in the GnomAD database, including 28,604 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.61 (28604 hom., cov: 32)
• Consequence: HLCS NM_001352514.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.72
• Publications: 3 publications found

Genes affected

HLCS (HGNC:4976): (holocarboxylase synthetase) This gene encodes an enzyme that catalyzes the binding of biotin to carboxylases and histones. The protein plays an important role in gluconeogenesis, fatty acid synthesis and branched chain amino acid catabolism. Defects in this gene are the cause of holocarboxylase synthetase deficiency. Multiple alternatively spliced variants, encoding the same protein, have been identified.[provided by RefSeq, Jun 2011]

HLCS Gene-Disease associations (from GenCC):

• holocarboxylase synthetase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.729 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HLCS	NM_001352514.2	c.195+1910T>C		intron_variant	Intron 1 of 10	ENST00000674895.3	NP_001339443.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HLCS	ENST00000674895.3	c.195+1910T>C		intron_variant	Intron 1 of 10		NM_001352514.2	ENSP00000502087.2

Frequencies

GnomAD3 genomes AF: 0.610 AC: 92683 AN: 151938 Hom.: 28579 Cov.: 32

Gnomad AFR AF: 0.555

Gnomad AMI AF: 0.610

Gnomad AMR AF: 0.704

Gnomad ASJ AF: 0.642

Gnomad EAS AF: 0.749

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.622

Gnomad MID AF: 0.623

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.621

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.610 AC: 92761 AN: 152056 Hom.: 28604 Cov.: 32 AF XY: 0.613 AC XY: 45532 AN XY: 74332

African (AFR) AF: 0.556 AC: 23027 AN: 41450

American (AMR) AF: 0.704 AC: 10749 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.642 AC: 2228 AN: 3472

East Asian (EAS) AF: 0.749 AC: 3874 AN: 5172

South Asian (SAS) AF: 0.592 AC: 2856 AN: 4822

European-Finnish (FIN) AF: 0.622 AC: 6583 AN: 10580

Middle Eastern (MID) AF: 0.626 AC: 184 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41391 AN: 67974

Other (OTH) AF: 0.623 AC: 1314 AN: 2110

Alfa AF: 0.586 Hom.: 3901

Bravo AF: 0.618

Asia WGS AF: 0.620 AC: 2155 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.23
DANN	Benign	0.33
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1571700; hg19: chr21-38336834;